U.S. patent number 4,503,049 [Application Number 06/461,411] was granted by the patent office on 1985-03-05 for diphosphonic acid derivatives and pharmaceutical preparations containing them.
This patent grant is currently assigned to Schering Aktiengesellschaft. Invention is credited to Helmut Biere, Irmgard Boettcher, Clemens Rufer.
United States Patent |
4,503,049 |
Biere , et al. |
March 5, 1985 |
Diphosphonic acid derivatives and pharmaceutical preparations
containing them
Abstract
Diphosphonic acid derivatives of Formula I ##STR1## wherein R is
hydrogen, an alkali metal atom, an alkaline earth metal atom, or an
alkyl group of 1-4 carbon atoms and A is derived from a carboxylic
acid having anti-inflammatory and antiphlogistic activity and
containing an aromatic or heteroaromatic group, of Formula II are
pharmacologically efficacious compounds.
Inventors: |
Biere; Helmut (Berlin,
DE), Rufer; Clemens (Berlin, DE),
Boettcher; Irmgard (Basel, CH) |
Assignee: |
Schering Aktiengesellschaft
(Berlin and Bergkamen, DE)
|
Family
ID: |
6154493 |
Appl.
No.: |
06/461,411 |
Filed: |
January 27, 1983 |
Foreign Application Priority Data
|
|
|
|
|
Jan 27, 1982 [DE] |
|
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3203308 |
|
Current U.S.
Class: |
514/80; 514/90;
514/91; 514/94; 514/102; 514/108; 548/119; 549/220; 562/21;
987/162; 514/92; 514/100; 514/107; 548/113; 548/414; 562/13;
562/22; 987/104; 987/155; 987/164; 987/362; 987/60; 987/154 |
Current CPC
Class: |
C07F
9/65527 (20130101); A61P 29/00 (20180101); C07F
9/404 (20130101); C07F 9/4056 (20130101); A61P
3/00 (20180101); A61P 43/00 (20180101); C07F
9/3882 (20130101); C07F 9/386 (20130101); C07F
9/65031 (20130101); C07F 9/5728 (20130101) |
Current International
Class: |
C07F
9/00 (20060101); C07F 9/38 (20060101); C07F
9/655 (20060101); C07F 9/40 (20060101); C07F
9/6503 (20060101); C07F 9/572 (20060101); A61K
031/66 (); A61K 033/665 (); C07F 009/38 (); C07F
009/65 () |
Field of
Search: |
;260/932
;548/113,119,414 ;549/220 ;424/200,203,204 |
Foreign Patent Documents
Other References
Worms et al., J. Anorg. Allg. Chem., vol. 457, (1979), pp.
209-213..
|
Primary Examiner: Raymond; Richard L.
Attorney, Agent or Firm: Millen & White
Claims
What is claimed is:
1. A diphosphonic acid derivative of the formula ##STR10## wherein
R is hydrogen, an alkali metal atom, an alkaline earth metal atom,
or alkyl of 1-4 carbon atoms,
X is hydrogen, methyl, or ethyl, and
B is phenyl substituted in the para-position by cyclohexyl, or
1-pyrrolinyl and, optionally, additionally substituted in the
meta-position by fluorine or chlorine; phenyl substituted in the
meta-position by benzoyl or phenoxy; or phenyl substituted in the
ortho-position by 2,4-dichlorophenoxy or
2,6-dichlorophenylamino.
2. A diphosphonic acid derivative of the formula ##STR11## wherein
R is hydrogen, an alkali metal atom, an alkaline earth metal atom,
or alkyl of 1-4 carbon atoms,
R.sup.1 is cyclohexyl or cyclopentylmethyl, and
Y is hydrogen or chlorine.
3. A diphosphonic acid derivative of the formula ##STR12## wherein
R is hydrogen, an alkali metal atom, an alkaline earth metal atom,
or alkyl of 1-4 carbon atoms,
X is hydrogen, methyl or ethyl, and ##STR13##
4. A diphosphonic acid derivative of the formula ##STR14## wherein
n is 1, 2, or 3,
R is hydrogen, an alkali metal atom, an alkaline earth metal atom,
or alkyl of 1-4 carbon atoms,
W and W' are identical or different and each is hydrogen, fluorine
or chlorine, and
one of V and V' is nitrogen and the other is methyne optionally
substituted by phenyl.
5. A diphosphonic acid derivative of the formula ##STR15## wherein
R is hydrogen, an alkali metal atom, an alkaline earth metal atom,
or alkyl of 1-4 carbon atoms, and
R.sup.2 is p-chlorobenzoyl or cinnamoyl.
6. 2-[1-(4-Chlorobenzoyl)-5-methoxy-2-me
thyl-3-indolyl]-1-hydroxyethane-1,1-bis(phosphonic acid dimethyl
ester), or
2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-3-indolyl]-1-hydroxyethane-1,1-d
iphosphonic acid, compounds of claim 5.
7. 2-(6-Methoxy-2-naphthyl)-1-hydroxypropane-1,1-bis(phosphonic
acid dimethyl ester), or
2-(6-methoxy-2-naphthyl)-1-hydroxypropane-1,1-diphosphonic acid,
compounds of claim 3.
8.
2-(11-Oxo-2-dibenz[b,f]oxepinyl)-1-hydroxyethane-1,1-bis(phosphonic
acid dimethyl ester), or
2-(11-oxo-2-benz[b,f]oxepinyl)-1-hydroxyethane-1,1-diphosphonic
acid, compounds of claim 3.
9.
(6-Chloro-5-cyclopentylmethyl-1-indanyl)hydroxymethanebis(phosphonic
acid diethyl ester), or
(6-chloro-5-cyclopentylmethyl-1-indanyl)hydroxymethanediphosphonic
acid, compounds of claim 2.
10. 2-[2-(2,6-Dichloro
phenylamino)phenyl]-1-hydroxyethane-1,1-bis(phosphonic acid
dimethyl ester), or
2-[2-(2,6-dichlorophenylamino)phenyl]-1-hydroxyethane-1,1-diphosphonic
acid, compounds of claim 1.
11. 2-[4-(4-Chlorophenyl)-1-
(4-fluorophenyl)-3-pyrazolyl]-1-hydroxyethane-1,1-bis(phosphonic
acid diethyl ester),
2-[4-(4-Chlorophenyl-1-(4-fluorophenyl)-3-pyrazolyl]-1-hydroxyethane-1,1-d
iphosphonic acid, or the disodium salt thereof, compounds of claim
4.
12.
2-[3-(4-Chlorophenyl)-1-phenyl-3-pyrazolyl]-1-hydroxyethane-1,1-b
is(phosphonic acid dimethyl ester), or
2-[3-(4-chlorophenyl)-1-phenyl-3-pyrazolyl]-1-hydroxyethane-1,1-diphosphon
ic acid, compounds of claim 4.
13. 3-[4-(4-Chlorophenyl)-1-(4
-fluorophenyl)-3-pyrazolyl]-1-hydroxypropane-1,1-bis(phosphonic
acid dimethyl ester, or
3-[4-(4-chlorophenyl)-1-(4-fluorophenyl)-3-pyrazolyl]-1-(hydroxypropane-1,
1-diphosphonic acid, compounds of claim 4.
14. A diphosphonic acid derivative of the formula ##STR16## wherein
R is hydrogen, an alkali metal atom, an alkaline earth metal atom,
or alkyl of 1-4 carbon atoms and
A is the structural moiety of a carboxylic acid, ACOOH, to which
the carboxy group is attached, wherein the carboxylic acid has
antiinflammatory or antiphlogistic activity and is cliprofen,
suprofen, indoprofen, carprofen, metiazic acid, bufezolac,
isofezolac, tiaprofenic acid, zomepirac, tolmetin, clopirac,
fenclozic acid, fentiazac or sulindac;
or when R is H, a physiologically acceptable salt thereof with an
organic base.
15. A pharmaceutical composition comprising an antiinflammatorily
effective amount of a compound of the formula ##STR17## wherein R
is hydrogen, an alkali metal atom, an alkaline earth metal atom, or
alkyl of 1-4 carbon atoms,
X is hydrogen, methyl, or ethyl, and
B is phenyl substituted in the para-position by cyclohexyl, or
1-pyrrolinyl and, optionally, additionally substituted in the
meta-position by fluorine or chlorine; phenyl substituted in the
meta-position by benzoyl or phenoxy; or phenyl substituted in the
ortho-position by 2,4-dichlorophenoxy or 2,6-dichlorophenylamino;
or ##STR18## wherein R is hydrogen, an alkali metal atom, an
alkaline earth metal atom, or alkyl of 1-4 carbon atoms,
R.sup.1 is cyclohexyl or cyclopentylmethyl, and
Y is hydrogen or chlorine; or ##STR19## wherein R is hydrogen, an
alkali metal atom, an alkaline earth metal atom, or alkyl of 1-4
carbon atoms,
X is hydrogen, methyl or ethyl, and ##STR20## wherein n is 1, 2, or
3,
R is hydrogen, an alkali metal atom, an alkaline earth metal atom,
or alkyl of 1-4 carbon atoms,
W and W' are identical or different and each is hydrogen, fluorine
or chlorine, and
one of V or V' is nitrogen and the other is methyne optionally
substituted by phenyl; or ##STR21## wherein R is hydrogen, an
alkali metal atom, an alkaline earth metal atom, or alkyl of 1-4
carbon atoms, and
R.sup.2 is p-chlorobenzoyl or cinnamoyl;
and a pharmacologically acceptable adjuvant.
16. A method of treating inflammation in a patient in need of such
treatment comprising administering to the patient an
antiinflammatorily effective amount of a diphosphonic acid
derivative of the formula ##STR22## wherein R is hydrogen, an
alkali metal atom, an alkaline earth metal atom, or alkyl of 1-4
carbon atoms and
A is the structural moiety of a carboxylic acid, ACOOH, to which
the carboxy group is attached, wherein the carboxylic acid has
antiinflammatory or antiphlogistic activity and A contains an
aromatic or heteroaromatic group;
or when R is H, a physiologically acceptable salt thereof with an
organic base.
17. A method of claim 16 wherein the patient is suffering from
arthritis.
18. A method of claim 16, wherein the diphosphonic acid derivative
is of the formula ##STR23## wherein R is hydrogen, an alkali metal
atom, an alkaline earth metal atom, or alkyl of 1-4 carbon
atoms,
X is hydrogen, methyl or ethyl, and
B is phenyl substituted in the para-position by isobutyl,
cyclohexyl, C.sub.1-4 -alkoxy, or 1-pyrrolinyl and, optionally,
additionally substituted in the meta-position by fluorine or
chlorine; phenyl substituted in the meta-position by benzoyl or
phenoxy; or phenyl substituted or in the ortho-position by
2,4-dichlorophenoxy or 2,6-dichlorophenylamino; or ##STR24##
wherein R is hydrogen, an alkali metal atom, an alkaline earth
metal atom, or alkyl of 1-4 carbon atoms,
R.sup.1 is cyclohexyl or cyclopentylmethyl, and
Y is hydrogen or chlorine; or ##STR25## wherein R is hydrogen, an
alkali metal atom, an alkaline earth metal atom, or alkyl of 1-4
carbon atoms,
X is hydrogen, methyl or ethyl, and ##STR26## wherein n is 1, 2, or
3,
R is hydrogen, an alkali metal atom, an alkaline earth metal atom,
or alkyl of 1-4 carbon atoms,
W and W' are identical or different and each is hydrogen, fluorine
or chlorine, and
one of V or V' is nitrogen and the other is methyne optionally
substituted by phenyl; or ##STR27## wherein R is hydrogen, an
alkali metal atom, an alkaline earth metal atom, or alkyl of 1-4
carbon atoms, and
R.sup.2 is p-chlorobenzoyl or cinnamoyl.
Description
The present invention relates to diphosphonic acid derivatives and
to pharmaceutical preparations containing them as active
ingredients.
SUMMARY OF THE INVENTION
It is an object of the invention to provide new compounds having
valuable pharmacological properties.
Upon further study of the specification and appended claims,
further objects and advantages of this invention will become
apparent to those skilled in the art.
These objects have been attained by providing diphosphonic acid
derivatives of Formula I ##STR2## wherein R is hydrogen, an alkali
metal atom, an alkaline earth metal atom, or alkyl of 1-4 carbon
atoms and
A is the residue of a carboxylic acid having anti-inflammatory and
antiphlogistic activity, containing an aromatic or heteroaromatic
group and being of Formula II
diphosphonic acid derivatives of Formula Ia ##STR3## wherein R is
as defined for Formula I,
X is hydrogen, methyl, or ethyl, and
B is phenyl substituted in the para-position by isobutyl,
cyclohexyl, alkoxy, or 1-pyrrolinyl and, optionally, substituted
additionally in the meta-position by fluorine or chlorine; or
phenyl substituted in the meta-position by benzoyl or phenoxy, or
phenyl substituted in the ortho-position by 2,4-dichlorophenoxy or
2,6-dichlorophenylamino;
diphosphonic acid derivatives of Formula Ib ##STR4## wherein R is
as defined in Formula I,
R.sup.1 is cyclohexyl or cyclopentylmethyl; and
Y is hydrogen or chlorine;
diphosphonic acid derivatives of Formula Ic ##STR5## wherein R and
X are as defined above, and ##STR6## diphosphonic acid derivatives
of Formula Id ##STR7## wherein n is 1, 2, or 3,
R is as defined in Formula I,
W and W', are identical or different, and each is hydrogen,
fluorine or chlorine, and
one of V and V' is nitrogen and the other is a methyne residue
optionally substituted by a phenyl group; and
diphosphonic acid derivatives of Formula Ie ##STR8## wherein R is
as defined in Formula I, and
R.sup.2 is p-chlorobenzoyl or cinnamoyl;
or, throughout, when R is H, a physiologically acceptable salt
thereof with an organic base.
DETAILED DISCUSSION
In the foregoing formulae, suitable cations include Na, K, Ca, Ba,
Sr, Mg, etc. and suitable alkyl groups include methyl, ethyl, the
propyls and the butyls. In B, the alkoxy groups generally have 1-4
C-atoms.
The phosphonic acid derivatives of Formula Ia are derived from
carboxylic acids having antiinflammatory and antiphlogistic
activity, of Formula II, which are known by their antiinflammatory
effectiveness, such as, for example, ibuprofen, butibufen, MK 830,
fluorbiprofen, alclofenac, pirprofen, ketoprofen, fenoprofen,
fenclofenac, or diclofenac. Carboxylic acids of a similar structure
and of good antiinflammatory activity, which are likewise suitable
for the preparation of diphosphonic acid derivatives of Formula I
include for example, cliprofen, suprofen, or indoprofen.
The compounds of Formula Ib are likewise derived from carboxylic
acids also distinguished by a good antiinflammatory and
antiphlogistic activity, for example, BL 2365, clidanac, or
6-chloro-5-cyclopentylmethyl-1-indanecarboxylic acid.
The carboxylic acids forming the basis for the phosphonic acid
derivatives of Formula Ic are, as is known, likewise of similarly
good effectiveness, for example, benoxaprofen, cicloprofen,
naproxen, or isoxepac. Similarly highly effective carboxylic acids,
which are likewise suitable for preparing diphosphonic acid
derivatives of Formula I, are carprofen and metiazic acid.
Suitable starting materials for the production of the diphosphonic
acid derivatives of Formula Id include, for example, trifezolac,
pirazolac, or lonazolac. Structurally similar phosphonic acid
derivatives of Formula I can be prepared by reacting
antiinflammatorily and antiphlogistically active carboxylic acids
of Formula II, for example, bufezolac or isofezolac.
The phosphonic acid derivatives of Formula Ie are derived, for
example, from the highly effective carboxylic acids such as
indomethacin or cinmetacin.
Other highly active carboxylic acids of Formula II likewise
suitable for producing phosphonic acid derivatives of Formula I
include, for example, tiaprofenic acid, zomepirac, tolmetin,
clopirac, fenclozic acid, fentiazac, or sulindac, etc.
Especially preferred compounds are those of the Formulae Ia-Ie and
the examples below.
As can be seen, there are many compounds of Formula II which are
antiinflammatorily or antiphlogistically active which can provide A
groups which are contemplated equivalents of the specific such
groups exemplified herein. All of these are included in this
invention. In essence, this invention provides a structural
modification to acids ACOOH by which they are made to possess the
advantageous properties described herein. Many such acids of the
Formula A--COOH and possessing the requisite antiinflammatory or
antiphlogistic activity are known and described in T. J. Shen,
Nonsteroidal Anti-inflammatory Agents in Burger's Medicinal
Chemistry 4. Ed. 1981, Part III, pages 1205-1272.
The compounds of this invention, as do the carboxylic acids of
Formula II
exhibit pronounced antiinflammatory and antiarthritic activity.
However, the compounds of this invention are distinguished over
these compounds in that they are capable, inter alia, to affect the
productive and destructive power of bone cells
(osteoblasts/osteoclasts) in such a way that curative effects can
clearly be proven to exist in rats with induced arthritis.
This antiarthritic activity of the compounds of this invention
forms the basis for therapy of rheumatoid arthritis,
osteoarthritis, ankylosing spondylitis, and other related diseases,
especially of the collagen and the skeletal system (e.g.,
osteoporosis, Paget's disease, etc.). Moreover, the phosphonates
can be utilized in a therapeutically meaningful fashion as good
complexing agents for calcium in all cases where a disturbed
calcium metabolism has been recognized as cause for a disease, for
example in cardiovascular disorders, ectopic calcifications,
etc.
The compounds can be employed in the form of their full alkyl
esters, di-monoesters (half esters)--but preferably in the form of
the free phosphonic acids and/or their physiologically compatible
salts with alkali or alkaline earth hydroxides or with compatible
organic bases, eg. sodium hydroxide, potassium hydroxide, calcium
hydroxide, piperazine or methylglucamine.
Suitable galenic formulations for enteral or parenteral
administration include capsules, tablets, dragees, suppositories,
and also injection solutions and dermal preparations. Also, local
application is possible for the treatment of dermal or systemic
diseases.
The medical specialties are prepared in the usual way by converting
the active agents into the desired forms of application with
suitable additives, e.g., solutions, lotions, ointments, creams, or
plasters. In the thus-formulated medicines, the concentration of
active compound is dependent on the type of application. In the
case of lotions and ointments, an active agent concentration of
0.1% to 10% is preferably employed. Administration is as
conventional with such topical formulations, e.g., as with a
hydrocortisone cream.
The novel corticoids are also suitable furthermore in the form of
capsules, tablets, or dragees, etc., containing preferably 10-500
mg of active agent and being administrable orally (e.g., at daily
dosages of 1-50 mg/kg), e.g., analogously to the known agent
indometacine or naproxene.
Conventional excipients are pharmaceutically acceptable organic or
inorganic carrier substances suitable for parenteral, enteral or
topical application to mammals, including humans, which do not
deleteriously react with the active compounds. Suitable
pharmaceutically acceptable carriers include but are not limited to
water, salt solutions, alcohols, gum arabic, vegetable oils,
polyethylene glycols, gelatine, lactose, amylose, magnesium
stearate, talc, silicic acid, viscous paraffin, perfume oil, fatty
acid monoglycerides and diglycerides, pentaerythritol fatty acid
esters, hydroxy-methylcellulose, polyvinyl pyrrolidone, etc. The
pharmaceutical preparations can be sterilized and if desired mixed
with auxiliary agents, e.g., lubricants, preservatives,
stabilizers, wetting agents, emulsifiers, salts for influencing
osmotic pressure, buffers, coloring, flavoring and/or aromatic
substances and the like which do not deleteriously react with the
active compounds.
For parenteral application, particularly suitable are injectable
sterile solutions, preferably oily or aqueous solutions, as well as
suspensions, emulsions, or implants, including suppositories.
Ampoules are convenient unit dosages.
For enteral application, particularly suitable are tablets,
dragees, suppositories or capsules having talc and/or a
carbohydrate carrier or binder or the like, the carrier preferably
being lactose and/or corn starch and/or potato starch. A syrup,
elixir or the like can be used wherein a sweetened vehicle is
employed. Sustained release compositions can be formulated
including those wherein the active compound is protected with
differentially degradable coatings, e.g., by microencapsulation,
multiple coatings, etc.
Dosages for a given host for a given indication can be determined,
e.g., by customary comparison of the activities of the subject
compound and of a known agent by means of an appropriate,
conventional pharmacological protocol.
The phosphonates of this invention can be prepared according to
methods which are well known to those skilled in the art and
disclosed, e.g., in Houben-Weyl, "Methoden der organischen Chemie"
(Methods of Organic Chemistry) Georg Thieme publishers, Stuttgart,
4th edition (1963) XII/1: 453 et seq. whose disclosures are
incorporated by reference herein; such methods are represented in
the schematic below wherein an acyl phosphonate of Formula III
wherein A, and R are as defined above, is reacted in the presence
of a base, with a dialkyl phosphite of Formula IV
wherein R is as defined above, and optionally saponifying the
thus-formed esters, and optionally converting the acids into the
salts thereof. ##STR9##
Examples of bases suitable for conducting the process of this
invention include secondary amines, e.g., diethylamine,
dipropylamine, diisopropylamine, morpholine, or piperidine. The
reaction is conducted in inert organic solvents, e.g., ethers (e.g.
diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran) or
chlorinated hydrocarbons (e.g. dichloromethane, tetrachloroethane,
chloroform, or carbon tetrachloride).
The optionally subsequently effected saponification of the esters
can take place with mineral acids (e.g. semiconcentrated
hydrochloric acid or sulfuric acid). The cleavage reaction occurs
in an especially gentle fashion in an inert solvent (for example
one of the above-mentioned chlorinated hydrocarbons) with
trimethylsilyl iodide. For the salt formation, the free acids are
reacted as usual conventionally with the corresponding bases.
The starting compounds of Formula II required for the process of
this invention can be prepared conventionally from the
corresponding acid chlorides by reaction with dialkyl phosphites of
Formula III. The acid chlorides are all known or fully
conventionally preparable.
These syntheses illustrated in the schematic chart will be
explained in greater detail in the following practical examples
with reference to typical representatives.
Without further elaboration, it is believed that one skilled in the
art can, using the preceding description, utilize the present
invention to its fullest extent. The following preferred specific
embodiments are, therefore, to be construed as merely illustrative,
and not limitative of the remainder of the disclosure in any way
whatsoever. In the following example(s), all temperatures are set
forth uncorrected in degrees Celsius; unless otherwise indicated,
all parts and percentages are by weight.
EXAMPLE 1
At -7.degree. C., a suspension of 3.70 g of
2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-3-indolyl]-1-hydroxyethene-phosp
honic acid dimethyl ester (U.S. Pat. No. 4,014,997) in 20 ml of
tetrahydrofuran is combined with a solution of 1.08 g of dimethyl
phosphite and 0.63 g of diethylamine and allowed to stand for 3
hours at -7.degree. C. and then 16 hours at -15.degree. C. The
thus-precipitated product is then vacuum-filtered, thus obtaining
3.2 g of
2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-3-indolyl]-1-hydroxyethane-1,1-b
is(phosphonic acid dimethyl ester), mp 163.degree. C.
EXAMPLE 2
16.6 g of 2-(6-methoxy-2-naphthyl)propionic acid is stirred in 200
ml of diethyl ether with 16.2 g of phosphorus pentachloride for 60
minutes at 20.degree. C. The mixture is then concentrated, the
residue triturated with petroleum ether, and the product is 18 g of
2-(6-methoxy-2-naphthyl)propionyl chloride, mp 95.degree. C.
6.66 g of this acid chloride is combined in 100 ml of diethyl ether
with 3.99 g of trimethyl phosphite at 20.degree. C. and stored for
16 hours. The mixture is then concentrated and the residue
crystallized from diisopropyl ether, thus obtaining 3.63 g of
2-(6-methoxy-2-naphthyl)propionylphosphonic acid dimethyl ester, mp
59.degree. C.
A suspension of 5.0 g of this phosphonic acid ester in 70 ml of
diethyl ether is combined with 1.42 g of dimethyl phosphite and, at
-10.degree. C., with 0.26 g of dibutylamine in 10 ml of diethyl
ether. The mixture is cooled for 2 hours at -5.degree. C., the
crystallized product is vacuum-filtered, and the thus-obtained
product is 4.46 g of
2-(6-methoxy-2-naphthyl)-1-hydroxypropane-1,1-bis(phosphonic acid
dimethyl ester), mp 140.degree. C.
EXAMPLE 3
4.66 g of 2-(4-isobutylphenyl)propionic acid is agitated in 150 ml
of diethyl ether with 5.04 g of phosphorus pentachloride for one
hour at 20.degree. C. The mixture is then concentrated under
vacuum, thus obtaining 5.02 g of 2-(4-isobutylphenyl)propionyl
chloride. This compound is reacted with trimethyl phosphite as
described in Example 2, thus producing the dimethyl ester of
2-(4-isobutylphenyl)propionylphosphonic acid. The dimethyl ester is
reacted with dimethyl phosphite under the conditions described in
Example 2, thus obtaining the
2-(4-isobutylphenyl)-1-hydroxypropane-1,1-bis(phosphonic acid
dimethyl ester).
EXAMPLE 4
2.68 g of (11-oxo-2-dibenz[b,f]oxepinyl)acetic acid is dissolved in
9.15 ml of thionyl chloride and heated for 3 hours under reflux.
The mixture is then concentrated under vacuum, thus obtaining 3.04
g of (11-oxo-2-dibenz[b,f]oxepinyl)acetyl chloride. This acid
chloride is reacted under the conditions of Example 2 with
trimethyl phosphite, yielding 1.34 g of
2-(11-oxo-2-dibenz[b,f]oxepinyl)-1-hydroxyethenephosphonic acid
dimethyl ester, mp 118.degree. C. The resultant product is reacted
with dimethyl phosphite as described in Example 1, yielding the
2-(11-oxo-2-dibenz[b,f]oxepinyl)-1-hydroxyethane-1,1-bis(phosphonic
acid dimethyl ester), mp 133.degree. C.
EXAMPLE 5
3.22 g of 6-chloro-5-cyclopentylmethyl-1-indanecarboxylic acid is
heated under reflux for one hour with 10.5 ml of thionyl chloride
and concentrated, thus yielding 3.45 g of
6-chloro-5-cyclopentylmethyl-1-indanecarboxylic acid chloride as an
oil. The acid chloride is reacted with triethyl phosphite as
described in Example 2, yielding 3 g of
(6-chloro-5-cyclopentylmethyl-1-indanylidene)hydroxymethanephosphonic
acid diethyl ester, mp 126.degree. C. The resultant compound is
reacted with diethyl phosphite under the conditions mentioned in
Example 2, thus obtaining the
(6-chloro-5-cyclopentylmethyl-1-indanyl)hydroxymethane-bis(phosphonic
acid diethyl ester).
EXAMPLE 6
2-[N-Acetyl-N-(2,6-dichlorophenyl)amino]phenylacetic acid is
reacted with phosphorus pentachloride in diethyl ether to obtain
2-[N-acetyl-N-(2,6-dichlorophenyl)amino]phenylacetic acid chloride.
The acid chloride is then reacted with trimethyl phosphite under
the conditions described in Example 2, thus producing
2-[N-acetyl-N-(2,6-dichlorophenyl)amino]phenyl-1-hydroxyethene-1-phosphoni
c acid dimethyl ester; this compound is converted, under the
conditions of Example 1, with dimethyl phosphite into
2-[2-(2,6-dichlorophenylamino)phenyl]-1-hydroxyethane-1,1-bis(phosphonic
acid dimethyl ester).
EXAMPLE 7
2-[2-(2,6-Dichlorophenylamino)phenyl]-1-hydroxyethane-1,1-bis(phosphonic
acid dimethyl ester) is heated for 4 hours on a steam bath with
concentrated hydrochloric acid; the mixture is then diluted with
water, allowed to cool down, and the thus-separated product is
vacuum-filtered, thus obtaining
2-[2-(2,6-dichlorophenylamino)phenyl]-1-hydroxyethane-1,1-diphosphonic
acid.
EXAMPLE 8
2.18 g of
2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-3-indolyl]-1-hydroxyethane-1,1-b
is(phosphonic acid dimethyl ester) is combined in 15 ml of
tetrachloromethane at -5.degree. C. with 2.29 ml of
iodotrimethylsilane and stored for 4 hours at 0.degree. C. The
mixture is then concentrated under vacuum and combined with ice
water. The thus-obtained precipitate is triturated with
acetonitrile and vacuum-filtered, thus obtaining 1.92 g of
2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-3-indolyl]-1-hydroxyethane-1,1-d
iphosphonic acid, mp 202.degree. C.
EXAMPLE 9
Under the conditions of Example 7,
2-(6-methoxy-2-naphthyl)-1-hydroxypropane-1,1-bis(phosphonic acid
dimethyl ester) is hydrolyzed, yielding
2-(6-methoxy-2-naphthyl)-1-hydroxypropane-1,1-diphosphonic acid, mp
205.degree. C.
EXAMPLE 10
Under the conditions of Example 7,
2-(4-isobutylphenyl)-1-hydroxypropane-1,1-bis(phosphonic acid
dimethyl ester) is hydrolyzed, thus producing
2-(4-isobutylphenyl)-1-hydroxypropane-1,1-diphosphonic acid.
EXAMPLE 11
Under the conditions of Example 7,
2-(11-oxo-2-dibenz[b,f]oxepinyl)-1-hydroxyethane-1,1-bis(phosphonic
acid dimethyl ester) is reacted, yielding
2-(11-oxo-2-dibenz[b,f]oxepinyl)-1-hydroxyethane-1,1-diphosphonic
acid, mp 228.degree. C.
EXAMPLE 12
(6-Chloro-5-cyclopentylmethyl-1-indanyl)hydroxymethanebis(phosphonic
acid diethyl ester) is reacted under the conditions of Example 7,
yielding
(6-chloro-5-cyclopentylmethyl-1-indanyl)hydroxymethanediphosphonic
acid.
EXAMPLE 13
16.5 g of 4-(4-chlorophenyl)-1-(4-fluorophenyl)-3-pyrazoleacetic
acid is cooled in 400 ml of diethyl ether to -15.degree. C. and
combined with incremental portions of 14.6 g of phosphorus
pentachloride. The mixture is stirred at -15.degree. C. for 2.5
hours and at 0.degree. C. for another 2.5 hours. The clear solution
is then exhaustively concentrated under vacuum, the oily residue is
stirred together with petroleum ether (boiling range
40.degree.-60.degree. C.), and the product is 16 g of
4-(4-chlorophenyl)-1-(4-fluorophenyl)-3-pyrazoleacetic acid
chloride, mp 93.degree.-95.degree. C.
A solution of 17.5 g of
4-(4-chlorophenyl)-1-(4-fluorophenyl)-3-pyrazoleacetic acid
chloride in 100 ml of tetrahydrofuran is cooled to 10.degree. C.
and combined with 9.8 ml of triethyl phosphite. The mixture is
stirred for 3 hours at 10.degree.-15.degree. C., the solution is
concentrated under vacuum, and the oily residue is crystallized
from diisopropyl ether, thus obtaining 18.8 g (83.4%) of
2-[4-(4-chlorophenyl)-1-(4-fluorophenyl)-3-pyrazolyl]-1-hydroxyethenephosp
honic acid diethyl ester, mp 96.degree.-98.degree. C.
EXAMPLE 14
At 0.degree. C., a solution of 18 g of
2-[4-(4-chlorophenyl)-1-(4-fluorophenyl)-3-pyrazolyl]-1-hydroxyethenephosp
honic acid diethyl ester in 40 ml of tetrahydrofuran is added
dropwise to a solution of 5.7 g of diethyl phosphite and 4.6 ml of
diethylamine in 30 ml of tetrahydrofuran, and the mixture is
stirred for 5 hours at 0.degree.-5.degree. C. The mixture is
concentrated under vacuum, recrystallized from diethyl ether and
then recrystallized from carbon tetrachloride, thus obtaining 15.2
g (64.4%) of
2-[4-(4-chlorophenyl)-1-(4-fluorophenyl)-3-pyrazolyl]-1-hydroxyethane-1,1-
bis(phosphonic acid diethyl ester), mp 141.degree.-142.degree.
C.
EXAMPLE 15
11.8 g of
2-[4-(4-chlorophenyl)-1-(4-fluorophenyl)-3-pyrazolyl]-1-hydroxyethane-1,1-
bis(phosphonic acid diethyl ester) is stirred for one hour at room
temperature with 5 equivalents of iodotrimethylsilane in 50 ml of
carbon tetrachloride under nitrogen. The mixture is concentrated
under vacuum, the residue is combined with water and acetone,
stirred for another 30 minutes, and the thus-precipitated product
is recrystallized from ethanol. Yield: 8.0 g (84%) of
2-[4-(4-chlorophenyl)-1-(4-fluorophenyl)-3-pyrazolyl]-1-hydroxyethane-1,1-
diphosphonic acid, mp 202.degree.-204.degree. C.
EXAMPLE 16
0.59 g of
2-[4-(4-chlorophenyl)-1-(4-fluorophenyl)-3-pyrazolyl]-1-hydroxyethane-1,1-
bis(phosphonic acid diethyl ester) is combined with 4 ml of 63%
strength hydrobromic acid and heated for 2 hours to 100.degree. C.
The mixture is then diluted with water and allowed to cool down.
The resultant crude product is comminuted and recrystallized from
ethanol, yielding 0.37 g (77%) of
2-[4-(4-chlorophenyl)-1-(4-fluorophenyl)-3-pyrazolyl]-1-hydroxyethane-1,1-
diphosphonic acid, mp 201.degree.-203.degree. C.
EXAMPLE 17
A solution of 1.9 g of
2-[4-(4-chlorophenyl)-1-(4-fluorophenyl)-3-pyrazolyl]-1-hydroxyethane-1,1-
diphosphonic acid in 5 ml of dimethylformamide is combined with a
solution of 0.8 g of sodium bicarbonate in 10 ml of water and
stirred for 2 hours at room temperature. Then the thus-precipitated
product is vacuum-filtered, washed with a small amount of water,
and dried at 110.degree. C., yielding 1.6 g (76%) of
2-[4-(4-chlorophenyl)-1-(4-fluorophenyl)-3-pyrazolyl]-1-hydroxyethanedipho
sphonic acid disodium salt, mp above 300.degree. C.
EXAMPLE 18
[3-(4-Chlorophenyl)-1-phenyl-4-pyrazolyl]acetyl chloride is reacted
with trimethyl phosphite as described in Example 13 and worked up,
thus obtaining, in an 80% yield, the dimethyl ester of
2-[3-(4-chlorophenyl)-1-phenyl-3-pyrazolyl]-1-hydroxyethanephosphonic
acid, mp 174.degree. C. (diethyl ether).
EXAMPLE 19
2-[3-(4-Chlorophenyl)-1-phenyl-4-pyrazolyl]-1-hydroxyethanephosphonic
acid dimethyl ester is reacted with dimethyl phosphite as described
in Example 14 and worked up, thus obtaining in a 69% yield
2-[3-(4-chlorophenyl)-1-phenyl-3-pyrazolyl]-1-hydroxyethane-1,1-bis(phosph
onic acid dimethyl ester), mp 130.degree. C.
EXAMPLE 20
2-[3-(4-Chlorophenyl)-1-phenyl-4-pyrazolyl]-1-hydroxyethane-1,1-bis(phospho
nic acid dimethyl ester) is reacted as described in Example 15,
thus obtaining in a 78% yield
2-[3-(4-chlorophenyl)-1-phenyl-3-pyrazolyl]-1-hydroxyethane-1,1-diphosphon
ic acid, mp 199.degree. C.
EXAMPLE 21
(a) At 20.degree. C., 2.8 g of malonic acid dimethyl ester is added
to a suspension of 0.7 g of 80% sodium hydride in 40 ml of
1,2-dimethoxyethane and the mixture is agitated for 30 minutes.
Then a solution of 7.3 g of
3-bromomethyl-4-(4-chlorophenyl)-1-(4-fluorophenyl)pyrazole in 30
ml of 1,2-dimethoxyethane is added thereto, and the mixture is
stirred for another 12 hours. The reaction mixture is worked up as
usual, the residue is recrystallized from cyclohexane, and the
product is 4.2 g of
[4-(4-chlorophenyl)-1-(4-fluorophenyl)-3-pyrazolylmethyl]malonic
acid dimethyl ester, mp 123.degree. C.
(b) A solution of 0.9 g of
[4-(4-chlorophenyl)-1-(4-fluorophenyl)-3-pyrazolylmethyl]malonic
acid dimethyl ester in 2.5 ml of ethanol is combined with 12 ml of
2N aqueous sodium hydroxide solution and heated for 3 hours under
reflux. The mixture is allowed to cool, acidified with 2N
hydrochloric acid, the precipitate is recrystallized from
acetonitrile, and the thus-obtained product is 0.8 g of
[4-(4-chlorophenyl)-1-(4-fluorophenyl)-3-pyrazolylmethyl]malonic
acid, mp 188.degree. C.
(c) A solution of 3 g of
[4-(4-chlorophenyl)-1-(4-fluorophenyl)-3-pyrazolylmethyl]malonic
acid in 50 ml of chlorobenzene is heated under reflux until the
release of gas ceases (about 2.5 hours). The mixture is
concentrated under vacuum, the residue is recrystallized from
carbon tetrachloride, thus obtaining 2.2 g of
3-[4-(4-chlorophenyl)-1-(4-fluorophenyl)-3-pyrazolyl]propionic
acid, mp 131.degree. C.
(d) At 0.degree. C., 1.3 g of phosphorus pentachloride is added in
incremental portions to a mixture of 1.9 g of
3-[4-(4-chlorophenyl)-1-(4-fluorophenyl)-3-pyrazolyl]propionic acid
in 60 ml of diethyl ether; the mixture is agitated for 3 hours,
then concentrated, and the residue recrystallized from petroleum
ether, thus obtaining 1.85 g of
3-[4-(4-chlorophenyl)-1-(4-fluorophenyl)-3-pyrazolyl]propionic acid
chloride, mp 111.degree. C.
(e) At 0.degree. C., a solution of 0.7 g of trimethyl phosphite in
2 ml of diethyl ether is added dropwise to a solution of 1.85 g of
3-[4-(4-chlorophenyl)-1-(4-fluorophenyl)-3-pyrazolyl]propionic acid
chloride in 10 ml of diethyl ether. The mixture is allowed to stand
for 3 days, concentrated under vacuum, and the yield is 1.98 g of
3-[4-(4-chlorophenyl)-1-(4-fluorophenyl)-3-pyrazolyl]-1-oxopropane-1-phosp
honic acid dimethyl ester as an oil.
(f) At 0.degree. C., a solution of 1.98 g of
3-[4-(4-chlorophenyl)-1-(4-fluorophenyl)-3-pyrazolyl]-1-oxopropane-1-phosp
honic acid dimethyl ester in 15 ml of diethyl ether and 10 ml of
dichloromethane is added dropwise to a solution of 0.55 g of
dimethyl phosphite and 50 mg of diethylamine in 10 ml of diethyl
ether. The mixture is then stirred for 3 days at 0.degree. C.,
worked up as usual, and the residue recrystallized from ethanol,
thus obtaining 1 g of
3-[4-(4-chlorophenyl)-1-(4-fluorophenyl)-3-pyrazolyl]-1-hydroxypropane-1,1
-bis(phosphonic acid dimethyl ester), mp 131.degree. C.
EXAMPLE 22
At 0.degree. C., 0.34 g of iodotrimethylsilane is added to a
suspension of 0.22 g of
3-[4-(4-chlorophenyl)-1-(4-fluorophenyl)-3-pyrazolyl]-1-hydroxypropane-1,1
-bis(phosphonic acid dimethyl ester) in 4 ml of tetrachloromethane,
and the mixture is stirred for one hour at 0.degree. C. and another
2 hours at room temperature. The reaction mixture is then
concentrated and the residue recrystallized from ethanol, yielding
130 mg of
3-[4-(4-chlorophenyl)-1-(4-fluorophenyl)-3-pyrazolyl]-1-hydroxypropane-1,1
-diphosphonic acid, mp 223.degree. C.
The preceding examples can be repeated with similar success by
substituting the generically or specifically described reactants
and/or operating conditions of this invention for those used in the
preceding examples. From the foregoing description, one skilled in
the art can easily ascertain the essential characteristics of this
invention, and without departing from the spirit and scope thereof,
can make various changes and modifications of the invention to
adapt it to various usages and conditions.
* * * * *